INTRODUCTION:

"Dercum's disease," also referred to as adiposis dolorosa¹, lipomatosis dolorosa, Anders' syndrome, and Dercum-Vitaut syndrome², is delineated by the occurrence of painful fat tissue buildup¹, that vary in size from a rice grain to a pearl, walnut, or giant walnut³, in terms of multiplicity and localization¹. The pain from AD varies in type and intensity, can happen in flare-ups, and is linked to inflammation³well as fluid in adipose tissue called lipedema⁴which can lead to lymphedema. After adipose resection, seroma formation is common^3,4.

Francis Xavier Dercum, an American neurologist practicing in Philadelphia, provided the first description of the illness⁵.

In addition to describing the illness, he also came up with the word "adiposis dolorosa"^4,6. The sickness was also documented in Philadelphia by British physician Sir William Hale White⁷and American physician James Meschter Anders⁸.

Adiposis dolorosa is a disease with unknown causes and pathophysiology that has been linked to endocrine and lipid metabolism dysfunction^9,10. It is likely to be inherited and can be caused by multiple family lipomatosis¹¹. Painful lipomas can develop in any fat tissue¹¹, but are most commonly found on limbs and trunk¹² negatively impacting patients' quality of life. Postmenopausal obese women are more likely to acquire Dercum's disease than men¹.

Dercum's disease, also known as Juxta-articular adiposis dolorosa, Adiposis dolorosa, painful lipomatosis of morbus Dercum, fatty tissue rheumatism, Ander syndrome, or adiposalgia, has various possible names¹³. The aim of this review was to provide a comprehensive description of Dercum's disease, including its aetiology, epidemiology, classification, stages, signs and symptoms, diagnosis, histopathology, related disorders, standard therapies, investigational therapies, and complications.

ETIOLOGY:

Dercum's disease is a condition with an unclear cause, but there may be genetic factors at play as certain groups have a higher prevalence of the disease ¹⁴. It is believed to be caused by an autosomal dominant gene, although some families have only partial penetrance of the gene¹¹. A mitochondrial genome mutation has been ruled out as a probable cause of familial DD^15,16. Here are the theories proposed about the etiology of Adiposis dolorosa¹⁷.

Mechanical compression of nerves:

Some theories suggest that the pain in Dercum's disease is caused by swollen fatty deposits that compress and stretch nerves, but this notion has never been supported by histopathological research^18,19.

Neurological dysfunction:

Abnormal connections between peripheral autonomic and sensory neurons may be created in Dercum's disease, leading to the activation of pain receptors by transmitting aberrant autonomic signals to the spinal column. Pain in patients with dercum's disease may cause amplified sympathetic activity. The autonomic nervous system may be responsible for visceral pain, and substances that induce visceral pain may also cause pain in adipose tissue²⁰.

Dysfunction of adipose tissue:

Dercum's disease may not produce enough monounsaturated fatty acids, which can cause abnormal lipid metabolism. Adipose tissue of individuals experiencing pain shows an increase in long-chain monounsaturated fatty acids but not in unaffected adipose tissue²¹. Additionally, research has revealed a decrease in the conversion of glucose to neutral triglycerides²².

Endocrine dysfunction:

Dercum originally postulated that the etiology of the condition was rooted in an endocrine disorder, specifically thyroid gland atrophy⁶. However, Waldorf later proposed that the condition is brought on by a malfunction of the hypophyseal system²³.

Inflammation:

According to certain studies^14,24,25.Dercum's illness has an inflammatory origin. However, laboratory markers of inflammation such as C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) are typically normal in the disease, as per multiple studies ^{2,3,9,11,24,.26,27,28,29,30}. Compared to the control group, individuals diagnosed with Dercum's disease exhibited considerably elevated levels of multiple adipokines, such as adiponectin, IL-1, IL-8, IL-10, leptin, MCP, MIP-1, plasminogen activator inhibitor-1, and TNF. However, they had a tendency towards higher IL-13 and lower fractalkine levels, and there was also a significant reduction in MIP-1 expression³¹.

AFFECTED POPULATION:

Dercum's disease is a rare condition that primarily affects women, with a higher prevalence in those between the ages of 35 and 50^3,32. It is more common in Caucasians and is believed to occur in women at a ratio of 5-30:1 compared to men⁸. While Dercum hypothesized that the disease primarily affects postmenopausal women, recent studies show that 85.7% of patients experience it before menopause³.

CLASSIFICATION:

Dercum's disease is characterized by its classification into three distinct categories based on the distribution of fatty deposits, whether they are widespread or localized, as well as their location proximal to or within joints. Additionally, the size of lumps is taken into account in determining the subtypes of the disease. Specifically, the generalized diffuse type features small lumps, while all other types of the illness exhibit larger lumps ^17,27.

TYPE - I [Generalized diffuse form] - A condition characterised by diffusely distributed, painful adipocytes and the absence of identifiable lipomas.

TYPE - II [Generalized nodular form] - Pain in and around lipomas that is widespread throughout the body.

TYPE - III [Localized nodular form] - A few sites are affected by painful lipomas.

TYPE - IV [Juxta-articular form] - There are agonizing fat folds in or very close to major joints (the hip, knee, or elbow)¹⁷.

STAGES:

The condition of lipedema evolves through three stages and can be classified into three categories: the entire leg, the thighs, and the lower leg. In around 30% of cases, the limbs are also affected³³.

Stage 1 -The subcutaneous layer thickens and softens with small nodules and smooth skin.

Stage 2- The presence of larger nodules along with thickening and softening of the subcutis, coupled with uneven skin texture.

Stage 3- Disfiguring fat lobules appear on the inner thighs and knees, while gigantic nodules cause the subcutaneous layer to thicken and harden ³⁴.

SIGNS AND SYMPTOMS:

Dercum's disease is a condition that is characterized by excessive weight and painful fat tissue, with lipomas and uncomfortable fat commonly found in the extremities, trunk, pelvic region, and buttocks. Symptoms can range from bulky nodules to small, difficult-to-detect deposits, with varying degrees of palpable lipoma size and brittleness. Patients typically describe their symptoms as "burning" or "hurting," which can vary from paroxysmal impulsive pain episodes to hyperalgesia in subcutaneous fat and touch sensitivity. Dercum FX first reported these symptoms in 1892 ¹⁴.

Roux and Vitaut suggested 4 key symptoms for Dercum's disease in 1901³⁵

a. Generalised obesity

b. Weakness and susceptibility to fatigue (asthenia)

c. Multiple, painful, fatty masses

d. Psychiatric manifestations, including, depression, epilepsy, emotional instability, confusion, and dementia.

Occasionally, the four primary symptoms have served as diagnostic criteria ^{9,16,36,37,38,39,40,41.}.

Dercum's disease is a condition that is associated with a variety of symptoms including pain, fatty deposits, easy bruising, memory loss, anxiety, diabetes, bloating, constipation, shortness of breath, lethargy, weakness, joint pains, and muscle aches⁸. Lipomas typically affect the legs, arms, and trunk, with the thighs and buttocks being the most common regions. Obesity and chronic pain syndrome are often seen in patients with DD, along with psychiatric symptoms such as depression and sleep disorders. Cognitive impairment and potentially dementia may also be associated with the condition⁴².

Possible neurological symptoms in patients with DD include dementia, convulsions, depression, severe headaches, memory loss, and focus issues ⁴³. Mastalgia and headaches caused by scalp lipomas are rare signs of the condition^44,45. Additionally reported symptoms include ¹⁴:

a. Periods of elevated body temperature (37.5% to 39%) accompanied by deteriorating pain

b. Greater infection susceptibility, which also makes pain worse,

c. Increased hearing and a tendency to bruise, which may be caused by the development of fragile blood vessels within the fatty deposits.

Excess weight, hypoventilation (Pickwick) syndrome, dry mouth and eyes, irritable bowel syndrome, carpal tunnel syndrome, thyroid dysfunction, fibromyalgia, and a mild-to-moderate rise in cholesterol are only a few of the related disorders that have been seen in people with Dercum's disease ^{14, 46,47}.

DIAGNOSIS:

Based on symptoms:

The clinical diagnosis of the condition is based on observed symptoms and the exclusion of other related disorders⁴⁸. If specific symptoms are not present, diagnosis relies on a limited range of clinical criteria⁴⁹.

a. Generalised obesity or over weight.

b. The presence of persistent pain lasting for more than three months in the adipose tissue.

The article discusses the diagnosis of various conditions associated with fat accumulation, including Dercum's disease, lipoedema, fibromyalgia and Madelung's disease. Research on 53 patients with Dercum's disease found changes in certain substances in their blood and cerebrospinal fluid that suggest their involvement in pain signaling¹⁷. However, Currently, there are no laboratory tests that are specifically designed for the diagnosis of DD¹, and rheumatologic testing should be done to rule out other conditions⁴³.

Imaging appearance:

Magnetic resonance imaging (MRI) and ultrasound were used to identify lesions in the superficial subcutaneous fat, while the deep fat was unaffected. Imaging methods were more effective than physical examination in detecting lesions, indicating their asymptomatic nature. Tins et al. (2013) found that most lesions were oblong, less than 2 cm in diameter, and had a lengthwise orientation parallel to the skin. Ultrasound revealed hyperechoic lesions with no discernible flow on Doppler imaging and no surrounding edema. MRI showed a blush-like appearance with reduced T1-weighted signal and elevated water-sensitive signal. Larger lesions had a more uneven appearance, but symptomatic and asymptomatic lesions did not differ significantly⁵⁰. On computed tomography (CT) images, lipomas can be seen to be stalked or stuck inside swollen subcutaneous fat tissue⁵¹.

Histopathology:

While biomarkers associated with Dercum's disease remain unclear, a histological examination of the lipoma can confirm the benignity or lipomatous nature of the adipose tissue⁵². Adipose tissue in Dercum's disease may be less metabolically active due to the predominance of connective tissue and fibrosis. Multi-nucleated giant cells in Dercum's disease adipose tissue suggest the involvement of activated, pro-inflammatory macrophages in the formation of adipose tissue and in resistance to weight reduction⁵³. There is also evidence of an inflammatory component linked to obesity rather than Dercum's disease, as observed in a weaker inflammatory response in Dercum's disease adipose tissue compared to lean obese controls⁵⁴.

RELATED DISORDERS:

Fibromyalgia:

The condition is distinguished by recurrent episodes of myalgia and acute exhaustion. The ascertaining of a diagnosis is contingent upon the manifestation of pronounced fatigue⁵⁵. Fibromyalgia syndrome (FMS) is a chronic disorder characterized by widespread musculoskeletal pain, fatigue, sleep disturbances, cognitive dysfunction, and mood disorders. Its exact cause is unknown, and it is considered part of a group of related conditions known as central sensitivity syndromes⁵⁶.

Lipoedema:

Lipoedema is a chronic disorder that primarily affects women and causes symmetrical swelling of the lower extremities due to the buildup of subcutaneous adipose tissue. The condition typically develops during adolescence and worsens over time, causing soreness upon palpation. Those with morbid obesity and chronic lipoedema may also develop lipolymphoedema ⁵⁷a secondary mechanical insufficiency of the lymphatic system due to comorbid ambulation issues, which can lead to edematous fluid accumulation and ultimately pulmonary edema⁵⁸.

Panniculitis:

An inflammation of subcutaneous adipose tissue, is characterized by tender nodules of the skin and systemic symptoms. Following a skin biopsy, the diagnosis identifies any septal or lobular characteristics, as well as the quantity and type of subcutaneous inflammatory infiltrates (neutrophils, histiocytes, lymphocytes, granulomas) ⁵⁹.

Proteus syndrome:

Proteus syndrome is a rare condition caused by a mosaic activating mutation in the AKT1 oncogene, and it is characterized by the rapid and uneven growth of multiple tissue types, including skin, bones, blood vessels, fat, and connective tissue, which can occur rapidly and unpredictably⁶⁰.

Endocrine disorders associated with pain and obesity, eg. Hypothyroidism and Cushing’s syndrome:

Endocrine disorders can cause physical and psychological symptoms, including discomfort, obesity, and psychological impairments. Cushing's syndrome is characterized by joint pain and gradual fat development, particularly in the face, back, and trunk, along with mental symptoms such as depression, emotional immaturity, and irritability. Hypothyroidism can lead to excess weight and pain in the extremities. It's important to note that individuals with endocrine disorders may lack the fatty tissue that typically causes discomfort⁶¹.

Multiple symmetric lipomatosis:

Multiple symmetric lipomatosis is a condition characterized by the development of large, symmetrical fatty lumps throughout the body, primarily affecting men. It can be caused by a hereditary mitochondrial disease resulting from a mutation at position 8344 of the mitochondrial DNA tRNA gene ⁶². The lumps are generally not painful, and the condition is associated with alcohol consumption but not necessarily with obesity⁶³.

Neurofibromatosis type 1:

Lipomas and neurofibromas caused by NF1 gene mutations are diagnosed differently. Lipomas are typically painless, except in cases of degeneration ⁶⁴while subcutaneous neurofibromas can be painful and cause neurological problems. Pathologically, lipomas and neurofibromas are distinct ⁶⁵.

Adipose tissue tumours:

Lipomas can vary and some can be painful⁶⁰but malignant adipose tissue cutaneous neoplasms are rare and usually not painful. These neoplasms include liposarcomas, cutaneous spindle cell or pleomorphic lipomas, cutaneous angiolipoleiomyoma, and skin adenolipoma. In Dercum's disease, tumors can typically be identified because they are painless⁶⁶.

Multiple endocrine neoplasia I (MEN I):

Patients with multiple endocrine neoplasia I (MEN 1) may have multiple non painful subcutaneous tumors, such as multiple lipomas. Due to the fact that the lipomas are painless, Dercum's disease can be separated from MEN 1 with ease⁶⁷.

Myoclonic epilepsy with red ragged fibres (MERRF): MERRF syndrome can be differentiated from Dercum's disease due to the non-nociceptive nature of its lipomas⁶².

Familial multiple lipomatosis:

Familial multiple lipomatosis is a condition where painless lipomas develop, often in the arms and legs. It is associated with autosomal dominant inheritance, although penetrance can vary. Abnormalities in multiple lipomatosis have been linked to the 12q13-15 region, which includes the PALB2 and HMGA2 genes⁶⁸.

STANDARD THERAPIES:

Dercum's disease treatment is individualized and focused on managing pain rather than curing the disease¹. A combination of medicinal therapies, surgical procedures, and psychological counseling is recommended⁶⁹. Main pharmacological treatments involve analgesics, but patients are often resistant to non-steroidal anti-inflammatory drugs¹⁷.

Weight loss is ineffective for treating Dercum's disease pain ^12,70. Lignocaine infusions have been used for pain relief^71,72. Recent research has identified multiple sodium channels involved in pain regulation, some of which are resistant to tetrodotoxin. Lidocaine has a higher potency on these channels and can correct unbalanced sodium fluxes that cause neuropathic pain ^25.Ketamine infusions are also a potential alternative to lidocaine⁷³.

Ketamine is a versatile dissociative agent used in anesthesia. It can be administered alone to induce anesthesia or in combination with other agents for both induction and maintenance⁷⁴.

Corticosteroids:

Prednisone at a 20 mg daily dose has been reported to provide some pain relief in Dercum's disease patients ^75,76,77but some have experienced worsening pain⁴⁶. Intralesional treatment with methylprednisolone has been shown to improve juxtaarticular Dercum's disease⁷⁸. Corticosteroids may alleviate pain by blocking the actions of various chemicals in the body, but it is not clear whether this effect is due to anti-inflammatory properties since the disease does not have an inflammatory origin⁷⁹.

Other drugs:

Mexiletine helps reduce pain and has comparable benefits when taken orally⁷². Concurrent use is necessary to avoid harmful effects. Combining pilocarpine and topical lidocaine is beneficial ^2,69,70 and amitriptyline may help with pain management and mental health problems⁸⁰. The primary cause of the pain-relieving impact of TCAs is the suppression of norepinephrine reuptake⁸¹.

Surgical treatment:

When medications are ineffective, the painful lumps are excised or removed surgically using liposuction. Surgical excision is effective in relieving pain but is contraindicated in some patients and is associated with obesity-related morbidity, and lipomas usually return within a few months^69,82,83. Liposuction is a cosmetic surgery that can remove lipomas and alleviate pain, psychological issues, and deformities^{2,38,70,82,84}. It is effective in cases without significant fibrosis ^17,85. Dermolipectomy is a surgical option for individuals with chronic conditions and fibrosis. Both procedures are a tried-and-true option for pain relief^83,85,86.

INVESTIGATIONAL THERAPIES:

Several medications have shown positive results in individual published studies for treating Dercum's disease, including pregabalin, interferon-2b, metformin, corticosteroids, calcium-channel modulators, and infliximab with methotrexate ^{17,25,87,88,89}.

In one study, two patients with Dercum's disease and chronic hepatitis C were treated with interferon-2b and had long-term pain relief ⁸⁹. Although the exact mechanism of this action is unknown, it may involve: 1) Antiviral effects of the medication, 2) Interferon stimulates the production of endogenous substances, such as endorphins, 3) Interferon interferes with the cytokine production of tumor necrosis factor and interleukin-1, which are linked to cutaneous hyperalgesias.

Pregabalin:

Pregabalin is a drug that mimics a neurotransmitter similar to GABA and has analgesic effects by reducing neuronal excitability. It achieves this by inhibiting the production of neurotransmitters such as noradrenaline, substance P, and glutamate by reducing calcium ion influx to the nerve terminals. Pregabalin has been shown to be effective in relieving pain, improving sleep quality, and enhancing overall well-being^,90,91,92,93.

Deoxycholic acid:

Deoxycholic acid, approved for reducing submental fat, has been found to be highly effective in treating lipomas in patients with Dercum's disease⁹⁴. However, there are potential hazards such as severe vascular events, alopecia, and skin lesions. Medical practitioners should use caution when administering this drug, and personalized evaluations should be conducted to monitor for complications. Common adverse events associated with ATX-101, which contains deoxycholic acid, include pain, edema, brusing, numbness, erythema, and induration at the injection site⁹⁵.

Calcium-channel modulators:

Calcium-channel modulators prevent neuronal calcium channels from opening, thereby inhibiting the release of chemicals such as excitatory amino acids that are required for central sensitization. These medications are used for the treatment of neuropathic pain⁹⁶.

"Non-surgical procedures, including rapid cycling hypobaric pressure⁹⁷electrocutaneous stimulation with FREMS and MC5-A Calmare ⁴⁹and manual deep massage, have been shown to reduce masses, nodules, and tissue fluid in lipomatous regions. Another method, Subcutaneous Adipose Tissue Treatment (SAT) can also be used to treat adipose tissue" ⁹⁸.

Rapid cycling hypobaric pressure:

A pilot study with 10 participants indicates that rapid cycling hypobaric pressure may be effective in reducing pain for people with Dercum's disease. This technique reduces tissue swelling, improves blood flow, and increases oxygen levels in the affected area⁹⁷, Fluctuations in pressure lead to modifications in both hot and cold temperatures. The body consistently adjusts to these variations and diverse patterns of low-pressure air, which pose a physical challenge for every cell in the body, similar to the effects of exercise which may explain why it can reduce pain^97.99,.

Frequency Rhythmic Electrical Modulation System (FREMS):

FREMS is an electrotherapy that regulates electrical stimulation through a software-driven mechanism. The wide range of frequencies used, mainly within the 1-50 Hz range, can promote healthy brain circuits and reduce illness interference. In lipedema, increased blood flow through FREMS therapy may reduce pain caused by hypoxia, inflammation, and adipocyte necrosis¹⁰⁰. Vascular endothelial growth factor released during therapy may further enhance blood flow and reduce hypoxia in painful adipose tissue¹⁰¹.

MC5-A Calmare Therapy:

A new electrocutaneous nerve stimulation device has been introduced for neuromodulation that is effective in treating chronic pain that is hard to treat, according to early tests^102,103. However, patients with pacemakers, aneurysm clips, automated defibrillators, skull plates, vena cava clips, untreated pain, epilepsy, or pregnant women should not use the device. Electrodes should not be placed on the carotid sinus or on the skull of these individuals, and a cost-benefit analysis should be conducted prior to use¹⁰⁴.

Subcutaneous Adipose Tissue Treartment (SAT):

Women with lipoedema who underwent deep SAT treatment showed a 0.4 kg reduction in persistent leg fat as measured by DXA scan⁹⁸. SAT treatment alters fat structure, enhances functionality ¹⁰⁵, and may restore normal fat metabolism¹⁰⁶. Manual SAT treatment improved the shape of fat tissue and decreased masses and nodules in cases of lipoedema and DD⁹⁸. Other treatments for fat diseases include phototherapy at 660 nm and human growth hormone to reduce the size of fatty deposits known as "buffalo humps" in people with acquired immunodeficiency syndrome¹⁰⁷.

Psychological support:

The objective of psychotherapy sessions and stress management is to minimize the likelihood of a surge in pain symptoms by limiting exposure to sources of psychological or physical stress¹³. Education and psychosocial interventions to help patients and families cope with the illness and its complications, and also to prevent relapses¹⁰⁸.

COMPLICATIONS:

Dercum disease may be accompanied or exacerbated by various symptoms including arthralgia, myxedema, cyanosis, headache, flushing, tremors, dyspnea, and tachypnea, particularly during painful episodes. Complications such as congestive myocardial infarction and hypertension are also possible^40,76.

While septic complications are rare, the cause of cytosteatonecrosis in Dercum disease may be vascular, possibly due to venous thrombosis caused by venous insufficiency or capillary microthrombosis resulting from arterial embolism of cardiac origin, such as Atrial fibrillation or Atrial flutter. Spontaneous necrosis may also occur as a result of Dercum disease¹⁰⁹.

CONCLUSION:

Dercum's disease is a rare and obscure condition typified by painful subcutaneous adipose tissue deposits, whose diagnosis is complicated by the indeterminate character of its symptoms, thereby often resulting in under diagnosis or misdiagnosis. The primary objective of treatment is symptom relief via supportive measures, while research is necessary to enhance our comprehension of the disease's pathogenesis and the efficacy of treatment alternatives. Early identification and diagnosis of DD are paramount in forestalling its progression and improving patients' quality of life.

CONFLICT OF INTEREST:

The authors have no conflicts of interest regarding this review.

REFERENCES:

1. Kucharz EJ, Kopeć-Mędrek M, Kramza J, Chrzanowska M, Kotyla P. Dercum's disease (adiposis dolorosa): a review of clinical presentation and management. Rheumatology. 2019; 57(5):281-287.

2. Bonatus TJ, Alexander AH. Dercum's disease (adiposis dolorosa): A case report and review of the literature. Clin Orthop Relat Res. 1986; (205):251-253.

3. Herbst KL, Asare-Bediako S. Adiposis Dolorosa Is More Than Painful Fat: The Endocrinologist. 2007 Nov; 17(6):326–34.

4. Dercum FX. A subcutaneous connective tissue dystrophy of the arms and back, associated with symptoms resembling myxoedema. 1888.

5. Patel DA, Swan KG. Francis Xavier Dercum: a man for all seasons. Ann Clin Transl Neurol. 2014; 1(3):233-237.

6. Dercum FX. Three cases of a hitherto unclassified affection resembling in its grosser aspects obesity, but associated with special nervous symptoms--adiposis dolorosa. 1. The American Journal Of The Medical Sciences (1827-1924). 1892 nov 1; 104(6):521.

7. White WH. A Case of Adiposis Dolorosa. BMJ. 1899; 2(2031):1533-1534.

8. Anders JM. A Text-book of the Practice of Medicine. WB Saunders Company; 1897.

9. Blomstrand R, Juhlin L, Nordenstam H, Ohlsson R, Werner B, Engström J. Adiposis dolorosa associated with defects of lipid metabolism. Acta dermato-venereologica. 1971; 51(4):243-250.

10. Pimenta WP, Paula FJ, Dick-de-Paula I, Piccinato CE, Monteiro CM, Brandao-Neto J, et al. Hormonal and metabolic study of a case of adiposis dolorosa (Dercum's disease). Brazilian Journal of Medical and Biological Research= Revista Brasileira de Pesquisas Medicas e Biologicas. 1992; 25(9):889-893.

11. Campen R, Mankin H, Louis DN, Hirano M, Maccollin M. Familial occurrence of adiposis dolorosa. Journal of the American Academy of Dermatology. 2001; 44(1):132-136.

12. Harris K, Davies K, Dumont S, Stephenson BM. A pain in the groin. Lancet (London, England). 1997; 350(9074):334.

13. Lemaitre M, Aubert S, Chevalier B, Jannin A, Bourry J, Prévost G, et al. Rare Forms of Lipomatosis: Dercum's Disease and Roch-Leri Mesosomatous Lipomatosis. Journal of Clinical Medicine. 2021; 10(6):1292.

14. Brorson H, Fagher B. Dercums sjukdom. Fettvävsreumatism orsakad av immunförsvarsreaktion? [Dercum's disease. Fatty tissue rheumatism caused by immune defense reaction?]. Lakartidningen. 1996; 93(15):1430-1436.

15. Holme E, Larsson NG, Oldfors A, Tulinius M, Sahlin P, Stenman G. Multiple symmetric lipomas with high levels of mtDNA with the tRNA(Lys) A-->G(8344) mutation as the only manifestation of disease in a carrier of myoclonus epilepsy and ragged-red fibers (MERRF) syndrome. American Journal of Human Genetics. 1993; 52(3):551-556.

16. Lemont H, Picciotti J, Pruzansky J. Dercum's disease. Journal of the American Podiatry Association. 1979; 69(6):389-391.

17. Hansson E, Svensson H, Brorson H. Review of Dercum's disease and proposal of diagnostic criteria, diagnostic methods, classification and management. Orphanet Journal of Rare Diseases. 2012; 7:23.

18. Dalziel K. The nervous system and adipose tissue. Clinics in Dermatology. 1989; 7(4):62-77.

19. Mella BA. Adiposis dolorosa. University of Michigan Medical Center Journal. 1967; 33(2):79-81.

20. Fagher B, Monti M, Nilsson-Ehle P, Akesson B. Fat-cell heat production, adipose tissue fatty acids, lipoprotein lipase activity and plasma lipoproteins in adiposis dolorosa. Clinical Science (London, England: 1979). 1991; 81(6):793-798.

21. Taniguchi A, Okuda H, Mishima Y, Nagata I, Oseko F, Hara M, et al. A case of adiposis dolorosa: lipid metabolism and hormone secretion. International Journal of Obesity. 1986; 10(4):277-281.

22. Szypula I, Kotulska A, Szopa M, Pieczyrak R, Kucharz EJ. Adiposis dolorosa with hypercholesterolemia and premature severe generalized atherosclerosis. Wiadomosci Lekarskie (Warsaw, Poland: 1960). 2009; 62(1):64-65.

23. Waldorf NW. An original clinical interpretation of Dercum’s disease (adiposis dolorosa). Endocrinology. 1924; 8:51-60.

24. Kirpila J, Ripatti N. Adipositas dolorosa juxta-articularis: Dercum's disease och dess behandling [Adiposis dolorosa juxta-articularis: Dercum's disease and its therapy]. Nordisk Medicin. 1958; 59(10):358-360.

25. Lange U, Oelzner P, Uhlemann C. Dercum's disease (Lipomatosis dolorosa): successful therapy with pregabalin and manual lymphatic drainage and a current overview. Rheumatology International. 2008; 29(1):17-22.

26. Eisman J, Swezey RL. Juxta-articular adiposis dolorosa: what is it? Report of 2 cases. Annals of the Rheumatic Diseases. 1979; 38(5):479-482.

27. Kosseifi S, Anaya E, Dronovalli G, Leicht S. Dercum's disease: an unusual presentation. Pain Medicine (Malden, Mass.). 2010; 11(9):1430-1434.

28. Margherita G. Considerazioni su di un caso di adiposi dolorosa post-traumatica associate ad une frattura patologica [Considerations on a case of post-traumatic adiposis dolorosa associated with a pathologic fracture]. Rassegna di Neuropsichiatria e Scienze Affini. 1964; 18:211-218.

29. Steiner J, Schiltz K, Heidenreich F, Weissenborn K. Lipomatosis dolorosa--ein häufig übersehenes Krankheitsbild [Lipomatosis dolorosa--a frequently overlooked disease picture]. Der Nervenarzt. 2002; 73(2):183-187.

30. Tiesmeier J, Warnecke H, Schuppert F. An uncommon cause of recurrent abdominal pain in a 63-year-old obese woman. German Medical Weekly (1946). 2006; 131(9):434-437.

31. Herbst KL, Coviello AD, Chang A, Boyle DL. Lipomatosis-associated inflammation and excess collagen may contribute to lower relative resting energy expenditure in women with adiposis dolorosa. International Journal of Obesity. 2009; 33(9):1031-1038.

32. Wortham NC, Tomlinson IP. Dercum's disease. Skinmed. 2005; 4(3):157-164.

33. Herpertz U. [Treatment of edema with special reference to lymph drainage therapy]. Zeitschrift Fur Lymphologie. Journal of Lymphology. 2022; 9(2)

34. Rapprich S, Dingler A, Podda M. Liposuction is an effective treatment for lipedema-results of a study with 25 patients. J Dtsch Dermatol Ges. 2011; 9(1):33-40.

35. Roux J, Vitaut M. Maladie de Dercum (Adiposis dolorosa). Rev Neurol (Paris). 1901; 9:881-888.

36. Hovesen E. Adipositas dolorosa (Dercums syndrom) [Adiposis doloros (Dercum's syndrome)]. Nordisk Med. 1953; 50(28):971-973.

37. Iwane T, Maruyama M, Matsuki M, Ito Y, Shimoji K. Management of intractable pain in adiposis dolorosa with intravenous administration of lidocaine. Anesth Analg. 1976; 55(2):257-259.

38. Jensen JJ, Kiilerich S. Et tilfaelde af adiposis dolorosa--morbus Dercum [A case of adiposis dolorosa--Dercum's disease]. Ugeskr Laeger. 1991; 153(50):3⁵⁶4.

39. Pouliquen A, Baize P, Lebosse J, Fellion G. What remains of Dercum's disease? Ann Med Psychol. 1984; 142(5):730-737.

40. Sierro C, Suter PM, Vetter W. Schmerzhafte Lipome?! [Painful lipoma?]. Praxis. 2002; 91(4):129-132.

41. Spaeth W. Adiposis dolorosa; with report of a case. N C Med J. 1949; 10(5):269-273.

42. Cantone M, Lanza G, Pennisi M, Bella R, Schepis C, Siragusa M, Barone R, Ferri R. Prominent neurological involvement in Dercum disease. J Neurol. 2017; 264(4):796-798.

43. Macaron N, Arbiser J. Adiposis dolorosa. Available at: http://www.emedicine.com/derm/topic839.htm. Accessed [2003].

44. Trentin C, Di Nubila B, Cassano E, Bellomi M. A rare cause of mastalgia: Dercum's disease (adiposes dolorosa). Tumori. 2008; 94(5):762-764.

45. Kawale J, Mahore A, Dange N, Bhoyar K. Adiposis dolorosa of scalp presenting with severe headache: an unusual case. J Headache Pain. 2010; 11(6):539-541.

46. Greenbaum SS, Varga J. Corticosteroid-induced juxta-articular adiposis dolorosa. Arch Dermatol. 1991; 127(2):231-233.

47. Skagen K, Petersen P, Kastrup J, Nørgaard T. The regulation of subcutaneous blood flow in patients with Dercum's disease. Acta Derm Venereol. 1986; 66(4):337-339.

48. Kling DH. Juxta-articular adiposis dolorosa: its significance and relation to Dercum's disease and osteo-arthritis. Arch Surg. 1937; 34(4):599-630.

49. Martinenghi S, Caretto A, Losio C, Scavini M, Bosi E. Successful Treatment of Dercum's Disease by Transcutaneous Electrical Stimulation: A Case Report. Medicine (Baltimore). 2015; 94(24):e950.

50. Tins BJ, Matthews C, Haddaway M, Cassar-Pullicino VN, Lalam R, Singh J, Tyrrell PN. Adiposis dolorosa (Dercum's disease): MRI and ultrasound appearances. Clin Radiol. 2013; 68(10):1047-1053.

51. Petscavage-Thomas JM, Walker EA, Bernard SA, Bennett J. Imaging findings of adiposis dolorosa vs. massive localized lymphedema. Skeletal Radiol. 2015; 44(6):839-847.

52. Wang XQ, Wang XQ, Hsu ATYW, Goytain A, Ng TLT, Nielsen TO. A Rapid and Cost-Effective Gene Expression Assay for the Diagnosis of Well-Differentiated and Dedifferentiated Liposarcomas. J Mol Diagn. 2021; 23(3):274-284.

53. Herbst RS, Johnson DH, Mininberg E, Carbone DP, Henderson T, Kim ES, Blumenschein G Jr, Lee JJ, Liu DD, Truong MT, Hong WK, Tran H, Tsao A, Xie D, Ramies DA, Mass R, Seshagiri S, Eberhard DA, Kelley SK, Sandler A. Phase I/II trial evaluating the anti-vascular endothelial growth factor monoclonal antibody bevacizumab in combination with the HER-1/epidermal growth factor receptor tyrosine kinase inhibitor erlotinib for patients with recurrent non-small-cell lung cancer. J Clin Oncol. 2005; 23(11):2544-2555.

54. Hansson E, Svensson H, Stenram U, Brorson H. Histology of adipose tissue inflammation in Dercum's disease, obesity and normal weight controls: a case control study. J Inflamm (Lond). 2011; 8(1):24.

55. Wolfe F, Clauw DJ, Fitzcharles MA, Goldenberg DL, Katz RS, Mease P, Russell AS, Russell IJ, Winfield JB, Yunus MB. The American College of Rheumatology preliminary diagnostic criteria for fibromyalgia and measurement of symptom severity. Arthritis Care Res (Hoboken). 2010; 62(5):600-610.

56. Mohammed Hadi Alosami, Faiq I. Gorial, Dalia Mohammed Jasim. Fibromyalgia Syndrome and Acne Vulgaris: A New Link. Research J. Pharm. and Tech. 2019; 12(4):1632-1636.

57. Fonder MA, Loveless JW, Lazarus GS. Lipedema, a frequently unrecognized problem. J Am Acad Dermatol. 2007; 57(2 Suppl):S1-S3.

58. Peled AW, Slavin SA, Brorson H. Long-term Outcome After Surgical Treatment of Lipedema. Ann Plast Surg. 2012; 68(3):303-307.

59. Diaz Cascajo C, Borghi S, Weyers W. Panniculitis: definition of terms and diagnostic strategy. Am J Dermatopathol. 2000; 22(6):530-549.

60. Wolfswinkel EM, Imahiyerobo TA, McComb JG, Sanchez-Lara PA, Urata MM. Proteus Syndrome with a Cranial Intraosseous Lipoma. J Craniofac Surg. 2017; 28(8):e771-e773.

61. Rubin E, Faber JL, editors. Pathology. 3rd edition. Philadelphia: Lippincott-Raven; 1999.

62. Kobayashi J, Nagao M, Miyamoto K, Matsubara S. MERRF syndrome presenting with multiple symmetric lipomatosis in a Japanese patient. Intern Med. 2010; 49(5):479-482.

63. Veger HT, Ravensbergen NJ, Ottenhof A, da Costa SA. Familial multiple lipomatosis: a case report. Acta Chir Belg. 2010; 110(1):98-100.

64. Miraglia E, Moliterni E, Iacovino C, Roberti V, Laghi A, Moramarco A, Giustini S. Cutaneous manifestations in neurofibromatosis type 1. Clin Ter. 2020; 171(5):e371-e377.

65. Ferner RE. The neurofibromatoses. Pract Neurol. 2010; 10(2):82-93.

66. Mentzel T. Cutaneous lipomatous neoplasms. Semin Diagn Pathol. 2001; 18(4):250-257.

67. Marini F, Falchetti A, Del Monte F, Carbonell Sala S, Gozzini A, Luzi E, Brandi ML. Multiple endocrine neoplasia type 1. Orphanet J Rare Dis. 2006; 1:38.

68. Mejía Granados DM, de Baptista MB, Bonadia LC, Bertuzzo CS, Steiner CE. Clinical and Molecular Investigation of Familial Multiple Lipomatosis: Variants in the HMGA2 Gene. Clin Cosmet Investig Dermatol. 2020; 13:1-10.

69. Reece PH, Wyatt M, O'Flynn P. Dercum's disease (adiposis dolorosa). J Laryngol Otol. 1999; 113(2):174-176.

70. DeFranzo AJ, Hall JH Jr, Herring SM. Adiposis dolorosa (Dercum's disease): liposuction as an effective form of treatment. Plast Reconstr Surg. 1990; 85(2):289-292.

71. Atkinson RL. Intravenous lidocaine for the treatment of intractable pain of adiposis dolorosa. Int J Obes. 1982; 6(4):351-357.

72. Petersen P, Kastrup J. Dercum's disease (adiposis dolorosa). Treatment of the severe pain with intravenous lidocaine. Pain. 1987; 28(1):77-80.

73. Eliason AH, Seo YI, Murphy D, Beal C. Adiposis Dolorosa Pain Management. Federal Practitioner. 2019; 36(11):529-533.

74. Jassim M. Khalaf Albozachri, Hayder M. AL-Tomah, Osamah N. Wali, Yasser J. Jameel. A Comparison Study of Nefopam ketamine, Tramadol ketamine and Xylazine ketamine anesthesia in Rabbit. Research J. Pharm. and Tech. 2019; 12(5):2439-2442.

75. Palmer ED. Dercum's disease: adiposis dolorosa. Am Fam Physician. 1981; 24(5):155-157.

76. Brodovsky S, Westreich M, Leibowitz A, Schwartz Y. Adiposis dolorosa (Dercum's disease): 10-year follow-up. Ann Plast Surg. 1994; 33(6):664-668.

77. Spota BB, Brage D. Cortisone therapy of Dercum's disease. El Dia Medico. 1952; 24(73):1930-1932.

78. Weinberger A, Wysenbeec AJ, Pinkhas J. Juxta-articular adiposis dolorosa associated with rheumatoid arthritis. Report of 2 cases with good response to local corticosteroid injection. Clin Rheumatol. 1987; 6(3):446-448.

79. Cross SA. Pathophysiology of pain. Mayo Clin Proc. 1994; 69(4):375-383.

80. Pardal Refoyo JL. Adiposis dolorosa (enfermedad de Dercum) [Adiposis dolorosa (Dercum's disease)]. Anales Otorrinolaringologicos Ibero-Americanos. 1996; 23(4):435-440.

81. Sansone RA, Sansone LA. Pain, pain, go away: antidepressants and pain management. Psychiatry (Edgmont). 2008; 5(12):16-19.

82. Berenguer B, de la Cruz L, de la Plaza R. Liposuction in atypical cases. Aesthetic Plast Surg. 2000; 24(1):13-21.

83. Held JL, Andrew JA, Kohn SR. Surgical amelioration of Dercum's disease: a report and review. J Dermatol Surg Oncol. 1989; 15(12):1294-1296.

84. Berntorp E, Berntorp K, Brorson H, Frick K. Liposuction in Dercum's disease: impact on haemostatic factors associated with cardiovascular disease and insulin sensitivity. J Intern Med. 1998; 243(3):197-201.

85. Wollina U, Goldman A, Heinig B. Microcannular tumescent liposuction in advanced lipedema and Dercum's disease. Giornale italiano di dermatologia e venereologia: organo ufficiale, Societa Italiana Di Dermatologia e Sifilografia. 2010; 145(2):151-159.

86. Bertheuil N, Huguier V, Beuzeboc M, Aillet S, Watier E. Knee dermolipectomy: a simple operation with significant functional improvement. Aesthetic Plastic Surgery. 2013; 37(1):117-120.

87. Łabuzek K, Liber S, Suchy D, Okopień B. A successful case of pain management using metformin in a patient with adiposis dolorosa. International Journal of Clinical Pharmacology and Therapeutics. 2013; 51(6):517-524.

88. Gonciarz Z, Mazur W, Hartleb J, Machniak M, Bednarek I, Mazurek U, Wilczok T. Interferon alfa-2b induced long-term relief of pain in two patients with adiposis dolorosa and chronic hepatitis C. Journal of Hepatology. 1997; 27(6):1141.

89. Singal A, Janiga JJ, Bossenbroek NM, Lim HW. Dercum's disease (adiposis dolorosa): a report of improvement with infliximab and methotrexate. Journal of the European Academy of Dermatology and Venereology: JEADV. 2007; 21(5):717.

90. Lesser H, Sharma U, LaMoreaux L, Poole RM. Pregabalin relieves symptoms of painful diabetic neuropathy: a randomized controlled trial. Neurology. 2004; 63(11):2104-2110.

91. Rosenstock J, Tuchman M, LaMoreaux L, Sharma U. Pregabalin for the treatment of painful diabetic peripheral neuropathy: a double-blind, placebo-controlled trial. Pain. 2004; 110(3):628-638.

92. Sabatowski R, Gálvez R, Cherry DA, Jacquot F, Vincent E, Maisonobe P, Versavel M, 1008-045 Study Group. Pregabalin reduces pain and improves sleep and mood disturbances in patients with post-herpetic neuralgia: results of a randomised, placebo-controlled clinical trial. Pain. 2004; 109(1-2):26-35.

93. Siddall PJ, Cousins MJ, Otte A, Griesing T, Chambers R, Murphy TK. Pregabalin in central neuropathic pain associated with spinal cord injury: a placebo-controlled trial. Neurology. 2006; 67(10):1792-1800.

94. Wipf A, Lofgreen S, Miller DD, Farah RS. Novel Use of Deoxycholic Acid for Adiposis Dolorosa (Dercum Disease). Dermatologic surgery: official publication for American Society for Dermatologic Surgery. 2019; 45(12):1718-1720.

95. Dayan SH, Humphrey S, Jones DH, Lizzul PF, Gross TM, Stauffer K, Beddingfield FC 3rd. Overview of ATX-101 (Deoxycholic Acid Injection): A Nonsurgical Approach for Reduction of Submental Fat. Dermatologic surgery: official publication for American Society for Dermatologic Surgery. 2016; 42 Suppl 1:S263-S270.

96. Baron R. Neuropathic pain: a clinical perspective. Handbook of Experimental Pharmacology. 2009; (194):3-30.

97. Herbst KL, Rutledge T. Pilot study: rapidly cycling hypobaric pressure improves pain after 5 days in adiposis dolorosa. Journal of Pain Research. 2010; 3:147-153.

98. Ibarra M, Eekema A, Ussery C, Neuhardt D, Garby K, Herbst KL. Subcutaneous adipose tissue therapy reduces fat by dual X-ray absorptiometry scan and improves tissue structure by ultrasound in women with lipoedema and Dercum disease. Clinical Obesity. 2018; 8(6):398-406.

99. S. Selva Priya. Dercum’s Disease (Adiposis Dolorosa). Int. J. Nur. Edu. and Research. 2018; 6(4): 435-438.

100.Fife CE, Maus EA, Carter MJ. Lipedema: a frequently misdiagnosed and misunderstood fatty deposition syndrome. Advances in Skin and Wound Care. 2010; 23(2):81-94.

101.Bevilacqua M, Dominguez LJ, Barrella M, Barbagallo M. Induction of vascular endothelial growth factor release by transcutaneous frequency modulated neural stimulation in diabetic polyneuropathy. Journal of Endocrinological Investigation. 2007; 30(11):944-947.

102.Marineo G. Untreatable pain resulting from abdominal cancer: new hope from biophysics? JOP: Journal of the Pancreas. 2003; 4(1):1-10.

103.Sabato AF, Marineo G, Gatti A. Scrambler therapy. Minerva Anestesiologica. 2005; 71(7-8):479-482.

104.Ricci M, Pirotti S, Scarpi E, Burgio M, Maltoni M, Sansoni E, Amadori D. Managing chronic pain: results from an open-label study using MC5-A Calmare® device. Supportive care in cancer: official journal of the Multinational Association of Supportive Care in Cancer. 2012; 20(2):405-412.

105.Lucassen GW, van der Sluys WL, van Herk JJ, Nuijs AM, Wierenga PE, Barel AO, Lambrecht R. The effectiveness of massage treatment on cellulite as monitored by ultrasound imaging. Skin research and technology: official journal of International Society for Bioengineering and the Skin (ISBS) [and] International Society for Digital Imaging of Skin (ISDIS) [and] International Society for Skin Imaging (ISSI). 1997; 3(3):154-160.

106.Thomas DM, Brown A, Dawson JA, Li P, Heymsfield SB, Allison DB. Letter to the Editor: Exceptional Data in Paper on "The effect of meridian massage on BM, BMI, WC and HC in simple obesity patients: a randomized controlled trial". World Journal of Acupuncture-Moxibustion. 2015; 25(1):66-67.

107.Rietschel P, Hadigan C, Corcoran C, Stanley T, Neubauer G, Gertner J, Grinspoon S. Assessment of growth hormone dynamics in human immunodeficiency virus-related lipodystrophy. The Journal of Clinical Endocrinology and Metabolism. 2001; 86(2):504-510.

108.Archana Das, Hiramoni Barman, Lt Col M Jayalakshmi. Burden and Psychological well-being among the primary Caregivers of Schizophrenia. Int. J. of Advances in Nur. Management. 2021; 9(2):113-120.

109.Haddad D, Athmani B, Costa A, Cartier S. Dercum's disease: a serious complication during a rare disease. Apropos of a case [Dercum's disease: a severe complication in a rare disease. A case report]. Annals of Plastic and Aesthetic Surgery. 2005; 50(3):247-250.

Received on 16.06.2023 Modified on 31.07.2023

Asian J. Res. Pharm. Sci. 2023; 13(4):287-295.

DOI: 10.52711/2231-5659.2023.00049